A murine model has been developed of graft-versus-host disease (GVHD) due to minor histocompatibility antigens (minor HA) in two strain combinations selected for H-2 identity and for mutual nonreactivity in MLC: C57BL/6-LP (H-2b combination) and B10.D2/nSn-BALB/c (H-2d combination).This model possesses many characteristics in common with human GVHD, including acute and chronic forms. This model has been used to systematically study the immune mechanisms that produce GVHD in response to minor HA. The histopathology of GVH skin disease has been described in a collaborative study with Dr. Richard Sontheimer, Dept. of Dermatology, Dallas, TX. The presence of cytolytic T lymphocytes (CTL) in mice with transplants does not correlate with GVH and may not represent the significant effector mechanism of GVH. A new assay of the proliferative response to minor HA has been developed to study the role of non-CTL in the pathogenesis of minor HA-GVHD. Congenic strains of mice developed between C57BL/10, LP, and 129 mice have been used to demonstrate that multiple minor H antigenic differences must exist between donor and recipient strains for GVH to develop. Studies are in progress to evaluate the immunoregulation of cellular responses to minor HA in mice with transplants. Attempts to study the proliferative response of spleen cells from mice with GVHD to recipient strain and third party antigens led to the demonstration that these spleen cells were unable to respond to foreign antigens in mixed lymphocyte culture. Further studies demonstrated that mice with minor antigen GVHD have an acquired form of severe combined immunodeficiency and are unable to develop either cell-mediated or humoral immunity to specific antigens. The specific mechanism of this immunodeficiency is under investigation using both in vivo and in vitro techniques. Using adoptive transfer methods, we have been able to transfer minor antigen GVHD to secondary recipients. The cells that transfer GVHD are Thy-1+, but the Lyt phenotype of the cells appears to be strain dependent; some are Lyt-1, while in other strains the cells are a combination of Lyt-1 and Lyt-2 + cells. Further work is in progress to identify the cells that transfer GVHD. (LB)